The reversible modulation of cadherin-based adhesion plays a critical role in epithelial tumor cell progression. Whereas most studies have focused on the regulation of classic cadherins in cancer, less attention has been paid to the importance of desmosomal cadherins. We recently showed that epidermal growth factor receptor (EGFR) inhibition results in the accumulation of desmosomal cadherins in oral squamous cell carcinoma (OSCC) cells, enhancing desmosome assembly and increasing intercellular adhesive strength. We hypothesized that EGFR inhibition interferes with desmosomal cadherin internalization and/or entry into a degradative pathway. Supporting this idea, EGFR inhibitors block accumulation of desmoglein 2 (Dsg2) in a cytoplasmic pool, correlated with inhibition of matrix metalloproteinase (MMP)-dependent processing of the Dsg2 ectodomain and tyrosine phosphorylation of its cytoplasmic domain. Furthermore, MMP-inhibition blocked internalization of Dsg2, but not E-cadherin, in highly invasive SCC68 cells, raising the possibility that regulation of desmosomal and classic cadherins can be uncoupled mechanistically. We propose a model whereby EGFR tyrosine phosphorylation and MMP-dependent cleavage cooperate to promote internalization and degradation of the desmosomal cadherin complex, leading to weakened adhesion, increased invasion and metastasis of OSCC. We will test this by: 1) using a combination of confocal microscopy, live cell imaging and biochemical analysis of OSCC to assess whether EGFR/MMP inhibition diverts desmosomal cadherins from a degradative pathway by preventing internalization and/or promoting endosome recycling of Dsg2/Dsc2, 2) defining the contribution of Dsg2 cytoplasmic domain and associated armadillo proteins to regulation of desmosomal cadherin cell surface expression and internalization, and 3) determining the contribution of MMP-dependent Dsg2 cleavage to internalization and degradation of the desmosomal cadherin complex in vitro and to tumor growth, invasion and metastasis in vivo. These studies will help to establish a paradigm for how desmosomal cadherins are regulated by signals in the tumor microenvironment of head and neck cancers. Results from this work will also have important implications for the future tailoring of therapeutic strategies based on their cadherin and MMP status.